Adenovirus-mediated herpes simplex virus type-1 thymidine kinase gene therapy suppresses oestrogen-induced pituitary prolactinomas

We tested the hypothesis that gene transfer using recombinant adenovirus ve ctors (RAds) expressing herpes simplex virus type 1 thymidine kinase (HSV1- TK) might offer an alternative therapeutic approach for the treatment of pi tuitary prolactinomas that do not respond to classical treatment strategies . HSV1-TK converts the prodrug ganciclovir (GCV) to GCV monophosphate, whic h is in turn further phosphorylated by cellular kinases to GCV triphosphate , which is toxic to proliferating cells. One attractive feature of this sys tem is the bystander effect, whereby untransduced cells are also killed. Ou r results show that RAd/HSV1-TK in the presence of GCV is nontoxic for the normal anterior pituitary (AP) gland in vitro, but causes cell death in the pituitary tumor cell lines GH3, a PRL/GH-secreting cell line, and AtT20, a corticotrophic cell line. We have used sulpiride- and oestrogen-induced la ctotroph hyperplasia within the rat AP gland as an in vivo animal model. In trapituitary infection of rats bearing oestrogen-induced lactotroph hyperpl asia, with RAd/HSV1-TK and subsequent treatment with GCV, decreases plasma PRL levels and reduces the mass of the pituitary gland. More so, there were no deleterious effects on circulating levels of other AP hormones, suggest ing that the treatment was nontoxic to the AP gland in situ. In summary, ou r results show that suicide gene therapy using the HSV1-TK transgene could be further developed as a useful treatment to complement current therapies for prolactinomas.